Stereoselective synthesis of key intermediates for the preparation of strobilurins

Article abstract of DOI:10.1016/j.mencom.2008.03.010

The highly stereoselective synthesis of benzyl and tert-butyldimethylsilyl ethers of 3-methyl-6-arylhexa-3(Z),5(E)-dienols, which are key intermediates in the syntheses of strobilurins A and X, has been developed.

Full text of DOI:10.1016/j.mencom.2008.03.010

Mendeleev
Communications
Mendeleev Commun., 2008, 18, 84–85
Stereoselective synthesis of key intermediates
for the preparation of strobilurins
Natalia Ya. Grigorieva,* Anatoly G. Smirnov, Viktor A. Popovsky and Andrei V. Stepanov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian
Federation. Fax: +7 499 135 5328; e-mail: ves@ioc.ac.ru
DOI: 10.1016/j.mencom.2008.03.010
The highly stereoselective synthesis of benzyl and tert-butyldimethylsilyl ethers of 3-methyl-6-arylhexa-3(Z),5(E)-dienols, which
are key intermediates in the syntheses of strobilurins A and X, has been developed.
Strobilurins 1 are antifungal antibiotics. About 20 representa-
5
3
1
NBut
2
4
tives of these compounds have been isolated and characterised;
they differ in the nature of the substituents at the aromatic ring.
The examples of the simplest strobilurins A (1A), B (1B) and
X (1X) and more complicated strobilurins C (1C), H (1H)
and N (1N) are shown in Scheme 1.
i–iii
v
X
R1
CH2OR2
OR2
4a,c
6a–c X = NBut
7a–c X = O
iv
R1
OH vi, vii
OMe
R2
MeO2C
R1
CH2OR2
R1
1
8a–c
3a–c
OR2
O
O
O
1A R1 = R2 = H
1B R1 = OMe, R2 = Cl
1H R1 + R2 =
a R1 = H, R2 = Bn
b R1 = OMe, R2 = Bn
c R1 = H, R2 = SiMe2But
O
1C R1 =
, R2 = H
OH
O
O
O
Scheme 2 Reagents and conditions: i, LDA/Et2O, 0 °C, 40 min; ii, 5a
or 5b/Et2O, –78 °C, 30 min, followed by heating to room temperature,
4 h; iii: 3% HCl, 20 min; iv, H2SO4 (cat.)/Me2CO–H2O (4:1), reflux, 5 h;
v, NaBH4/EtOH, room temperature; vi, Py SO3/THF, 0 °C, 3 h; vii, LiAlH4,
0 °C, 30 min, then room temperature, 20 h.
1X R1 = H, R2 = OMe
1N R1 + R2 =
OH
R1
R1
1
acetone in the presence of catalytic amounts of H2SO4. The con-
densation of compound 4a with (E)-4-methoxycinnamic aldehyde
5b occurs in a similar way via imine 6b to give dienal 7b.†
Note that condensations of aldimines with , -unsaturated
aldehydes have not been reported so far.
R2
CO2Me
R2
OR3
3
2
Scheme 1
The known methods for synthesising compounds 1 are non-
stereoselective and require a laborious separation of the isomers.1–3
This paper deals with the development of a highly stereoselec-
tive method for building the aryldiene skeleton of strobilurins.
As appears from the retrosynthetic analysis (see Scheme 1), ethers
3a and 3b, which are precursors of the simplest strobilurins A
(1A) and X (1X), respectively, are convenient objects for this
purpose.
To attain our goal, we used the methodology that is akin to
that previously developed for a highly stereoselective synthesis
of a (Z)-trisubstituted C=C bond4,5 and subsequently used to syn-
thesise low-molecular bioregulators of the polyprenols–dolichols
series,6,7 their modified analogues,8 and insect pheromones.9,10
According to this approach, the synthesis of compound 3a
(Scheme 2) starts with the cross-condensation of LDA-deprotonated
4-benzyloxybutanal tert-butylimine 4a with (E)-cinnamic aldehyde
5a to give rather stable imine 6a in a good yield. Compound 6a
converts into dienal 7a† only upon prolonged refluxing in aqueous
The stereochemistry of crystalline dienals 7a,b isolated in
80–85% total yields was established by NMR spectroscopy.
For example, C–H correlation and COSY methods provided
d and J parameters for the H atoms in the diene system of
compound 7b [d 6.98 (d, J 15 Hz), 7.05 (d, J 10 Hz), 7.20 (dd,
J1 10 Hz, J2 15 Hz)]. Of the two doublet signals shown above,
only the second signal with d 7.05 shows NOE (~10%) with
H(C1), which allows us to assign this signal to H(C3) and
conclude that the C2=C3 bond has the (E) configuration. This
conclusion is confirmed by the presence of a signal with d 9.5
1
in the H NMR spectrum of compound 7b and a signal with
d ~ 194 in its 13C NMR spectrum; these signals are typical of
the CHO group in (E)-enals. On the other hand, there are no
signals typical of the CHO group in (Z)-enals (d 10 in 1H NMR
spectra and d 191–192 in 13C NMR spectra).11,12
1
The second doublet signal in the H NMR spectra of dienal
7b (d 6.98) was assigned to H(C5). Its coupling constant with
H(C4) (15 Hz) suggests the (E) configuration of the C4=C5
bond. The stereochemistry of compound 7a was determined
in a similar way; the stereoselectivity of the synthesis was
almost 100%.
†
The structures of all new compounds were confirmed by elemental
analysis and physico-chemical methods (UV, IR, 1H and 13C NMR spectro-
scopy and mass spectrometry).
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© 2008 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2008, 18, 84–85
The complete preservation of the diene system configuration
reduction of the resulting 2(E),4(E)-dienals via corresponding
dienic alcohols and their sulfo esters gives trisubstituted
(Z,E)-dienes 3 with the complete preservation of the diene
system configuration.
in the reduction of compounds 7a,b to diene alcohols 8a,b†
(the yield is near 100%, Scheme 2) also follows from NMR
1
spectral data for the latter.‡ Note that the H NMR spectra of
these dienols contain a single signal of the CH2OH group with
d 4.15 and the 13C NMR spectra contain a single signal of this
group with d 69.2, which is also characteristic of (E)-enols.12
Similar proof was found for the preservation of the diene
system configuration in the reduction of compounds 8a,b via
the corresponding sulfonic esters (Scheme 2) to target dienes
3a,b.†,‡ Note that the 13C NMR spectra of the latter contain a
single signal of the Me group (d 24.5), which is also charac-
teristic of internal (Z)-methylolefins.12 No signals are observed
in higher field (d 15–19) where (E)-methylolefins usually
resonate.12
The conversion of dienes 3a,b into esters of type 2 (Scheme 1),
which can be smoothly transformed by a known method2 into
the corresponding strobilurins, requires the preliminary protec-
tion removal from the hydroxyl group. This operation can be
problematic in the case of Bn protection. Therefore, we also
synthesised diene 3c containing an acid-labile tert-butyldimethyl-
silyl group by the sequence of reactions shown in Scheme 2,
starting from (E)-cinnamic aldehyde 5a and imine 4c. Their
cross-condensation under the conditions described above after
treatment of the reaction mixture with aqueous (COOH)2 gave
dienal 7c in 65% yield;† the 2(E),4(E)-configuration of 7c was
confirmed in the same way as for dienals 7a,b.
This study was supported by the Russian Foundation for
Basic Research (grant no. 07-03-00454).
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The retention of the diene system configuration in the reduc-
tion of compound 7c to 8c† and then to 3c† (the total yield is
52%) was also confirmed as described for compounds 8a,b and
3a,b, respectively.
Thus, the condensation of (E)- , -unsaturated aldehydes with
aldimines occurs with high stereoselectivity; the subsequent
‡
The assignment of signals and determination of the configuration of the
system of diene bonds were carried out similarly to that of compound 7b.
Received: 6th September 2007; Com. 07/3009
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